The familial hypercholesterolemias are a group of hereditary disorders characterized by elevation of plasma low-density lipoproteins (LDL) and premature atherosclerosis. Based on clinical, laboratory and family studies, we have identified several variants of the disorder. Studies in cultured skin fibroblasts have revealed abnormalities in the metabolism of LDL, of cholesterol and fatty acids. We plan to study fibroblasts from several variants in an effort to evolve a classification based on a profile of biochemical abnormalities detected. Methods to be used include the incorporation of acetate into various lipid classes; the activities of certain enzymes of cholesterol and fatty acid synthesis; the binding, internalization and degradation of LDL; the measurements of rates of incorporation of 14C oleate into cholesteryl esters; the cellular concentrations of cholesterol and its esters. The in-vitro effect of various lipoproteins, cholesterol analogues and cholesterol derivatives on these parameters will be determined.